Loxapine

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Loxapine
Loxapine.svg
Loxapine ball-and-stick model from xtal 1977.png
Clinical data
Trade names Loxitane, Adasuve
AHFS/Drugs.com Monograph
MedlinePlus a682311
License data
Routes of
administration 		By mouth, inhalation, intramuscular
Drug class Antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 96.8% [2]
Metabolism Extensive Liver; active metabolites include amoxapine and 8-hydroxyloxapine. Inhibits P-gp and is a substrate of CYP1A2, CYP3A4 and CYP2D6 [2]
Elimination half-life 4 hours (oral); 7.61 hours (inhalation) [2]
Excretion Majority are excreted within 24 hours, main route through urine (conjugated metabolites), small amounts through the feces (unconjugated metabolites)
Identifiers
  • 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.016.215 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C18H18ClN3O
Molar mass 327.81 g·mol−1
3D model (JSmol)
Melting point 109 to 110 °C (228 to 230 °F)
  • Clc2ccc1Oc4c(/N=C(\c1c2)N3CCN(C)CC3)cccc4
  • InChI=1S/C18H18ClN3O/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18/h2-7,12H,8-11H2,1H3 Yes check.svgY
  • Key:XJGVXQDUIWGIRW-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)
Bottle containing loxapine capsules, a mid-potency antipsychotic. Loxapine.jpg
Bottle containing loxapine capsules, a mid-potency antipsychotic.

Loxapine, sold under the brand names Loxitane and Adasuve (inhalation only) among others, is a tricyclic [3] antipsychotic medication used primarily in the treatment of schizophrenia. The medicine is a member of the dibenzoxazepine class and structurally very similar to clozapine. Several researchers have argued that loxapine, initially classified as a typical antipsychotic, behaves as an atypical antipsychotic. [4]

Contents

Loxapine may be metabolized by N-demethylation to amoxapine, a tricyclic antidepressant. [5]

Medical uses

The US Food and Drug Administration (FDA) has approved loxapine inhalation powder for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. [6]

A brief review of loxapine found no conclusive evidence that it was particularly effective in patients with schizophrenia. [7] A subsequent systematic review considered that the limited evidence did not indicate a clear difference in its effects from other antipsychotics. [8]

Available forms

Loxapine can be taken by mouth. [9] It is also available as an intramuscular injection and as a powder for inhalation. [6] [9]

Side effects

Loxapine can cause side effects that are generally similar to that of other antipsychotic medications. These include, e.g., gastrointestinal problems (like constipation and abdominal pain), cardiovascular problems (like tachycardia), moderate likelihood of drowsiness (relative to other antipsychotics), [10] and movement problems (i.e. extrapyramidal symptoms [EPS]). [11] At lower dosages its propensity for causing EPS appears to be similar to that of atypical antipsychotics. [12] Although it is structurally similar to clozapine, it has much lower risk of agranulocytosis (which, even with clozapine, is 0.8%); however, mild and temporary fluctuations in blood leukocyte levels can occur. [13] [14] Abuse of loxapine has been reported. [15]

The inhaled formulation of loxapine carries a low risk for a type of airway adverse reaction called bronchospasm that is not thought to occur when loxapine is taken by mouth. [6]

Pharmacology

Mechanism of action

Some scientists say loxapine is a "mid-potency" typical antipsychotic. [14] However, unlike most other typical antipsychotics, it has significant potency at the 5HT2A receptor (6.6 nM), which is similar to atypical antipsychotics like clozapine (5.35 nM). The higher likelihood of EPS with loxapine, compared to clozapine, may be due to its higher affinity for the D2 receptor compared to clozapine, which has one of the lowest binding affinities at the D2 receptor of any antipsychotic. [14]

Loxapine (and metabolite) [16] [17]
SiteLOX AMX Tooltip Amoxapine
5-HT1A 2460ND
5-HT1B 388ND
5-HT1D 3470ND
5-HT1E 1400ND
5-HT2A 6.60.5
5-HT2C 132 (rat)
5-HT3 190ND
5-HT5A 780ND
5-HT6 3150
5-HT7 8840 (rat)
α1A 31ND
α1B 53ND
α2A 151ND
α2B 108ND
α2C 80ND
β1 10000+ND
β2 10000+ND
M1 120ND
M2 445ND
M3 211ND
M4 1270ND
M5 166ND
D1 54ND
D2 1121
D3 1921
D4 8.421
D5 75ND
H1 2.2–4.97.9–25
H2 208ND
H3 55000>100,000
H4 5050–87106,310
SERT Tooltip Serotonin transporter10000+58
NET Tooltip Norepinephrine transporter570016
DAT Tooltip Dopamine transporter10000+58
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Use as an Inhaled Agitation Medication

Loxapine has a relatively strong safety profile compared to similar antipsychotic drugs, such as quetiapine, olanzapine, and clozapine, with a relatively lower incidence of metabolic side-effects (although higher extrapyramial side-effects). [18] Given its strong safety profile and speed/efficacy when given intramuscularly for acute agitation, [19] an inhaled version of the drug (Adasuve) has been developed to be applied nasally for agitated patients needing to be rapidly de-escalated. [20]

Pharmacokinetics

Loxapine is metabolized to amoxapine, as well as its 8-hydroxy metabolite (8-hydroxyloxapine). [2] Amoxapine is further metabolized to its 8-hydroxy metabolite (8-hydroxyamoxapine), which is also found in the blood of people taking loxapine. [21] At steady-state after taking loxapine by mouth, the relative amounts of loxapine and its metabolites in the blood is as follows: 8-hydroxyloxapine > 8-hydroxyamoxapine > loxapine. [21]

The pharmacokinetics of loxapine change depending on how it is given. Intramuscular injections of loxapine lead to higher blood levels and area under the curve of loxapine than when it is taken by mouth. [21]

Chemistry

Loxapine is a dibenzoxazepine and is structurally very similar to clozapine, an atypical antipsychotic.

Chemical structures of loxapine and clozapine, with key differences highlighted. Loxapine and clozapine.svg
Chemical structures of loxapine and clozapine, with key differences highlighted.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. 1 2 3 4 Truven Health Analytics, Inc. DrugPoint System (Internet) [cited 2013 Sep 21]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  3. ↑ Popovic D, Nuss P, Vieta E (2015-04-01). "Revisiting loxapine: a systematic review". Annals of General Psychiatry. 14 15. doi: 10.1186/s12991-015-0053-3 . PMC   4391595 . PMID   25859275.
  4. ↑ Glazer WM (1999). "Does loxapine have "atypical" properties? Clinical evidence". The Journal of Clinical Psychiatry. 60 Suppl 10 (Suppl 10): 42–46. PMID   10340686.
  5. ↑ Cheung SW, Tang SW, Remington G (March 1991). "Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography". Journal of Chromatography. 564 (1): 213–221. doi:10.1016/0378-4347(91)80083-O. PMID   1860915.
  6. 1 2 3 "ADASUVE Package Insert" (PDF). Galen US Inc.
  7. ↑ "Clozapine and loxapine for schizophrenia". Drug and Therapeutics Bulletin. 29 (11): 41–42. May 1991. doi:10.1136/dtb.29.11.41. PMID   1747161. S2CID   27613339.
  8. ↑ Chakrabarti A, Bagnall A, Chue P, Fenton M, Palaniswamy V, Wong W, et al. (October 2007). Chakrabarti A (ed.). "Loxapine for schizophrenia". The Cochrane Database of Systematic Reviews. 2007 (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMC   7017975 . PMID   17943763.
  9. 1 2 "LOXITANE Package Insert" (PDF). Watson Laboratories, Inc.
  10. ↑ Taylor D, Paton C, Kapur S, Taylor D (2012). The Maudsley prescribing guidelines in psychiatry (11th ed.). Chichester, West Sussex: Wiley-Blackwell. ISBN   978-0-470-97948-8.
  11. ↑ Chakrabarti A, Bagnall A, Chue P, Fenton M, Palaniswamy V, Wong W, et al. (October 2007). "Loxapine for schizophrenia". The Cochrane Database of Systematic Reviews. 2007 (4): CD001943. doi:10.1002/14651858.CD001943.pub2. PMC   7017975 . PMID   17943763.
  12. ↑ Nordstrom K (2012). "Inhaled loxapine for rapid treatment of agitation in schizophrenia and bipolar disorder: An update". Neuropsychiatry. 2 (3): 253–260. doi:10.2217/npy.12.23. S2CID   39718567.
  13. ↑ DePaulo JR, Ayd FJ (March 1982). "Loxapine: fifteen years' clinical experience". Psychosomatics. 23 (3): 261–271. doi:10.1016/S0033-3182(82)73416-4. PMID   7041162.
  14. 1 2 3 Singh AN, Barlas C, Singh S, Franks P, Mishra RK (January 1996). "A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes". Journal of Psychiatry & Neuroscience : Jpn. 21 (1): 29–35. PMC   1188731 . PMID   8580115.
  15. ↑ Sperry L, Hudson B, Chan CH (March 1984). "Loxapine abuse". The New England Journal of Medicine. 310 (9): 598. doi:10.1056/NEJM198403013100920. PMID   6694719.
  16. ↑ Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  17. ↑ Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (February 2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology. 385 (2): 145–170. doi:10.1007/s00210-011-0704-0. PMID   22033803. S2CID   14274150.
  18. ↑ Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. (2019-09-14). "Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis". Lancet. 394 (10202). London, England: 939–951. doi:10.1016/S0140-6736(19)31135-3. ISSN   0140-6736. PMC   6891890 . PMID   31303314.
  19. ↑ Lebel C, Endomba FT, Chabridon G, Chauvet-Gélinier JC (2023-12-19). "Efficacy and Safety of Loxapine in Acute Agitation: A Systematic Review of Interventional Studies" . The Primary Care Companion for CNS Disorders. 25 (6). doi:10.4088/PCC.23r03552. ISSN   2155-7780. PMID   38134395.
  20. ↑ Popovic D, Nuss P, Vieta E (2015). "Revisiting loxapine: a systematic review". Annals of General Psychiatry. 14 15. doi: 10.1186/s12991-015-0053-3 . ISSN   1744-859X. PMC   4391595 . PMID   25859275.
  21. 1 2 3 Simpson GM, Cooper TB, Lee JH, Young MA (March 1978). "Clinical and plasma level characteristics of intramuscular and oral loxapine". Psychopharmacology. 56 (2): 225–232. doi:10.1007/BF00431855. PMID   417377. S2CID   21795809.
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